Drugs for treating respiratory and nasal disorders are frequently administered in aerosol compositions through the mouth or nose. One widely used method for dispensing such aerosol drug compositions involves making a suspension composition of the drug as a finely divided powder in a compressed liquefied gas known as a propellant. The suspension is stored in a sealed container capable of withstanding the pressure required to maintain the propellant as a liquid and the suspension is dispersed by activation of a dose metering valve affixed to the container.
A metering valve may be designed to consistently release a fixed, predetermined mass of the drug composition upon each activation. As the suspension is forced from the container through the dose metering valve by the vapour pressure of the propellant, the propellant rapidly vapourizes leaving a fast moving cloud of very fine particles of the drug composition. This cloud of particles is directed into the nose or mouth of the patient by a channeling device such as a cylinder or open ended cone.
Concurrently with the activation of the aerosol dose metering valve, the patient inhales the drug particles into the lungs or nasal cavity. Systems of dispensing drugs in this way are known as pressurised “metered dose inhalers” (MDIs).
The chemical species, S-fluoromethyl 6α,9α-difluoro-11β-hydroxy-16α-methyl-17-propionyloxy-3-oxoandrost-1,4-diene-17β-carbothioate is generically known as fluticasone propionate. Fluticasone propionate, first disclosed in U.S. Pat. No. 4,335,121, is a synthetic steroid of the glucocorticoid family. The related glucocorticoid, fluticasone furoate, S-fluoromethyl 6α,9α-difluoro-11β-hydroxy-16α-methyl-17-(2-furanylcarbonyl)oxy-3-oxoandrost-1,4-diene-17β-carbothioate, is disclosed in U.S. Pat. No. 6,787,532.
Glucocorticoid steroids have potent anti-inflammatory actions and are therefore useful in the treatment of a range of medical disorders and diseases. Fluticasone propionate is marketed for the treatment of asthma, allergic rhinitis, and skin disorders such as eczema, and fluticasone furoate is marketed for the treatment of allergic rhinitis. A combination product comprising fluticasone propionate and salmeterol xinafoate has also been approved for the treatment of asthma and chronic obstructive pulmonary disease (COPD).
Pressurized metered dose inhalers (MDIs) are widely used devices for the delivery of medicaments to the respiratory tract by inhalation via the oral and nasal routes. Though MDIs are used primarily for topical delivery of drugs to the respiratory tract for treatment of such diseases as asthma and chronic obstructive pulmonary disease (COPD), there is increasing interest in their use for systemic drug delivery. Classes of medicaments commonly delivered by MDIs include bronchodilators (e.g. beta-agonists and anti-cholinergics), corticosteroids, and anti-allergies.
MDI compositions are comprised of at least a medicament and a propellant, but the MDI compositions may further comprise one or more excipients other than propellant.
MDI compositions are generally characterized as either solutions or suspensions. A solution composition comprises the medicament dissolved or solubilized in propellant or in a mixture of propellant and one or more excipients. A suspension composition contains the medicament in the form of particles which are dispersed in the propellant or in a mixture of propellant and one or more other excipients.
Traditionally, the propellant system used in MDIs has consisted of one or more chlorofluorocarbons (CFCs), such as Freon 11 (CCl3F), Freon 12 (CCl2F2), and Freon 114 (CF2ClCF2Cl). However, the CFC propellants are now believed to provoke the degradation of stratospheric ozone and thus their production and use are being phased out.
Hydrofluoroalkane (HFA) propellants, particularly 1,1,1,2-tetrafluoroethane (HFA-134a) and 1,1,1,2,3,3,3,-heptafluoropropane (HFA-227), are currently favoured as non-ozone depleting alternatives to the CFC propellants for respiratory drug delivery. Other alternatives to CFCs have been proposed, including dimethyl ether and low molecular weight hydrocarbons, such as propane and butane.
The efficiency of an aerosol device, such as an MDI, is a function of the dose deposited at the appropriate site in the respiratory tract. Deposition is affected by several factors, of which one of the most important is the aerodynamic particle size. The distribution of aerodynamic particle sizes of solid particles and/or droplets in an aerosol can be characterized by their mass median aerodynamic diameter (MMAD, the diameter around which the mass aerodynamic diameters are distributed equally) and geometric standard deviation (GSD, the measure of variability of the aerodynamic particle diameters). Aerosol particles of equivalent MMAD and GSD have similar deposition in the respiratory tract irrespective of their composition.
The aerodynamic particle size depends upon a number of factors, including temperature, pressure, primary drug particle size, metering volume, actuator spray orifice diameter, excipient particle size and concentration.
For inhalation therapy, there is a preference for aerosols in which particles for inhalation have an MMAD of about 0.5 to 100 μm, depending on the intended site of deposition. Particles smaller than 0.5 μm may be exhaled. Particles larger than 100 μm may clog the metering valve or actuator orifice and may undergo suboptimal deposition.
For inhalation therapy targeting the lungs, there is a preference for aerosols in which the particles for inhalation have an MMAD of about 0.5 to 10 μm, more preferably about 0.5 to 5 μm, and most preferably about 0.5 to 3 μm. Particles larger than about 5 μm in diameter are primarily deposited by inertial impaction in the oropharynx, particles of about 0.5 to 5 μm in diameter are ideal for deposition in the conducting airways, and particles of about 0.5 to 3 μm in diameter are desirable for aerosol delivery to the lung periphery.
For inhalation therapy targeting the nose, there is a preference for aerosols in which the particles for inhalation have an MMAD of about 5 to 100 μm, more preferably about 5 to 50 μm, and most preferably about 5 to 25 μm.
Numerous methods are known in the art for the preparation of suspension aerosol compositions for MDIs. The known methods generally comprise the mixing of pre-formed medicament powders, which are of a size suitable for inhalation therapy, with propellant and optionally one or more other excipients. Control of the particle size distribution of the aerosol particles generated from the suspension aerosol composition is accomplished primarily via control of the particle size distribution of the medicament powders used to prepare the composition. Thus, considerable care is normally taken to avoid dissolution of the medicament powder in the excipients, as any dissolution of the medicament powder during manufacture of the composition would result in loss of particle size control. Conventional methods for generating medicament powders suitable for preparation of compositions for inhalation therapy, such as suspension aerosol compositions for MDIs, include milling (micronization), spray drying, and supercritical fluid recrystallization.
Suspension aerosol compositions are known in the art and examples of such compositions are disclosed in WO 04/069225, EP 518601, U.S. Pat. No. 5,182,097, EP 616523, EP 616525, EP 918507, U.S. Pat. No. 6,261,539, EP 920302, EP 605578, EP 536235, EP 513127 and EP 1248597. However, the compositions exemplified in the prior have certain limitations particularly when attempting to formulate a composition comprising fluticasone propionate in propellant HFA-134a.
The conventional processes of MDI manufacture are generally characterized as either “pressure filling” or “cold filling”. In pressure filling, the powdered medicament, optionally combined with one or more excipients, is placed in a suitable aerosol container capable of withstanding the vapour pressure of the propellant and fitted with a metering valve. The propellant is then forced as a liquid through the valve into the container. In an alternate process of pressure filling, the particulate drug is combined in a process vessel with propellant and optionally one or more excipients, and the resulting drug suspension is transferred through the metering valve fitted to a suitable MDI container. In cold filling, the powdered medicament, propellant which is chilled below its boiling point, and optionally one or more excipients are added to the MDI container, and a metering valve is fitted to the container. For both, pressure filling and cold filling processes, additional steps, such as mixing, sonication, and homogenization, are often advantageously included.
Patients often rely on medication delivered by MDIs for rapid treatment of respiratory disorders which are debilitating and in some cases even life threatening. Therefore, it is essential that each actuation and delivery of dose must be the same within very close limits. These dose limits of aerosol medication delivered to the patient must consistently meet the specifications claimed by the manufacturer and comply with the strict requirements of the regulatory authorities.